This invention relates to the use of certain pyridine-substituted benzanilide derivatives as potassium channel openers and to the treatment of diseases modulated by potassium channels. Additionally, this invention relates to novel compounds that are useful as potassium channel openers.
Ion channels are cellular proteins that regulate the flow of ions, including calcium, potassium, sodium and chloride, into and out of cells. These channels are present in all human cells and affect such processes as nerve transmission, muscle contraction and cellular secretion. Among the ion channels, potassium channels are the most ubiquitous and diverse, being found in a variety of animal cells such as nervous, muscular, glandular, immune, reproductive, and epithelial tissue. These channels allow the flow of potassium in and/or out of the cell under certain conditions. For example, the outward flow of potassium ions upon opening of these channels makes the interior of the cell more negative, counteracting depolarizing voltages applied to the cell. These channels are regulated, e.g., by calcium sensitivity, voltage-gating, second messengers, extracellular ligands, and ATP-sensitivity.
Potassium channels have now been associated with a number of physiological processes, including regulation of heartbeat, dilation of arteries, release of insulin, excitability of nerve cells, and regulation of renal electrolyte transport. Potassium channels are made by alpha subunits that fall into at least 8 families, based on predicted structural and functional similarities (Wei et al., Neuropharmacology 35(7): 805-829 (1997)). Three of these families (Kv, eag-related, and KQT) share a common motif of six transmembrane domains and are primarily gated by voltage. Two other families, CNG and SK/IK, also contain this motif but are gated by cyclic nucleotides and calcium, respectively. The three other families of potassium channel alpha subunits have distinct patterns of transmembrane domains. Slo family potassium channels, or BK channels have seven transmembrane domains (Meera et al., Proc. NatL Acad. Sci. U.S.A. 94(25): 14066-71 (1997)) and are gated by both voltage and calcium or pH (Schreiber et al., J Biol. Chem. 273: 3509-16 (1998)). Another family, the inward rectifier potassium channels (Kir), belong to a structural family containing two transmembrane domains, and an eighth functionally diverse family (TP, or xe2x80x9ctwo-porexe2x80x9d) contains two tandem repeats of this inward rectifier motif.
Potassium channels are typically formed by four alpha subunits, and can be homomeric (made of identical alpha subunits) or heteromeric (made of two or more distinct types of alpha subunits). In addition, potassium channels made from Kv, KQT and Slo or BK subunits have often been found to contain additional, structurally distinct auxiliary, or beta, subunits. These subunits do not form potassium channels themselves, but instead they act as auxiliary subunits to modify the functional properties of channels formed by alpha subunits. For example, the Kv beta subunits are cytoplasmic and are known to increase the surface expression of Kv channels and/or modify inactivation kinetics of the channel (Heinemann et al., J Physiol. 493: 625-633 (1996); Shi et al., Neuron 16(4): 843-852 (1996)). In another example, the KQT family beta subunit, minK, primarily changes activation kinetics (Sanguinetti et al., Nature 384: 80-83 (1996)).
Slo or BK potassium channels are large conductance potassium channels found in a wide variety of tissues, both in the central nervous system and periphery. They play a key role in the regulation of processes such as neuronal integration, muscular contraction and hormone secretion. They may also be involved in processes such as lymphocyte differentiation and cell proliferation, spermatocyte differentiation and sperm motility. Three alpha subunits of the Slo family have been cloned, i.e., Slo1, Slo2, and Slo3 (Butler et al., Science 261: 221-224 (1993); Schreiber et al., J Biol. Chem., 273: 3509-16 (1998); and Joiner et al., Nature Neurosci. 1: 462-469 (1998)). These Slo family members have been shown to be voltage and/or calcium gated, and/or regulated by intracellular pH.
Certain members of the Kv family of potassium channels were recently renamed (see Biervert, et al., Science 279: 403-406 (1998)). KvLQTl was re-named KCNQ1, and the KvLQT1-related channels (KvLR1 and KvLR2) were renamed KCNQ2 and KCNQ3, respectively. More recently, a fourth member of the KCNQ subfamily was identified (KCNQ4) as a channel expressed in sensory outer hair cells (Kubisch, et al., Cell 96(3): 437-446 (1999)).
KCNQ2 and KCNQ3 have been shown to be nervous system-specific potassium channels associated with benign familial neonatal convulsions (xe2x80x9cBFNCxe2x80x9d), a class of idiopathic generalized epilepsy (see, Leppert, et al., Nature 337: 647-648 (1989)). These channels have been linked to M-current channels (see, Wang, et al, Science 282: 1890-1893 (1998)). The discovery and characterization of these channels and currents provides useful insights into how these voltage dependent (Kv) potassium channels function in different environments, and how they respond to various activation mechanisms. Such information has now led to the identification of modulators of KCNQ2 and KCNQ3 potassium channels or the M-current, and the use of such modulators as therapeutic agents. The modulators are the subject of the present invention.
KCNQ4 (Kubsich et al., Cell 96(3): 437 (1999)), KCNQ5 (Kananura et aL, Neuroreport 11 (9):2063 (2000)), KCNQ 3/5 (Wickenden et al., Br. J. Pharma 132: 381 (2001)) and KCNQ6 have also recently been described.
The present invention provides pyridine-substituted benzanilide compounds, and phannaceutically acceptable salts thereof (xe2x80x9ccompounds of the inventionxe2x80x9d), which are useful in the treatment of diseases through the modulation of potassium ion flux through voltage-dependent potassium channels.
In one aspect, the present invention provides compounds having a structure according to Formula I: 
in which the symbol Ar1 represents a member selected from the group consisting of aryl, substituted aryl, heteroaryl and substituted heteroaryl. The letter X represents a member selected from the group consisting of O, S and N-R1, in which R1 is H, (C1-C8)alkyl, substituted (C1-C8)alkyl, heteroalkyl, substituted heteroalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, aryl(C1-C4)alkyl, substituted aryl(C1-C4)alkyl, CN, xe2x80x94C(O)R2, xe2x80x94OR3, xe2x80x94C(O)NR3R4, or xe2x80x94S(O)2NR3R4. The symbol R2 represents a member selected from the group consisting of (C1-C8)alkyl, substituted (C1-C8)alkyl, cycloalkyl, substituted cycloalkyl, heteroalkyl, substituted heteroalkyl, heterocyclyl, substituted heterocyclyl, substituted aryl, heteroaryl, substituted heteroaryl, aryl(C1-C4)alkyl and substituted aryl(C1-C4)alkyl. R3 and R4 are each members independently selected from the group consisting of hydrogen, (C1-C8)alkyl, substituted (C1-C8)alkyl, cycloalkyl, substituted cycloalkyl, heteroalkyl, substituted heteroalkyl, heterocyclyl, substituted heterocyclyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, aryl(C1-C4)alkyl and substituted aryl(C1-C4)alkyl. Alternatively, R3 and R4 can be combined with the nitrogen to which each is attached to form a 5-, 6- or 7-membered ring, optionally having additional heteroatoms at the ring vertices. The letter Y represents a member selected from the group consisting of halogen, C1-C4 alkyl, C1-C4 substituted alkyl, xe2x80x94OCH3 and 13 OCF3.
In another aspect, the present invention provides pharmaceutical compositions comprising a pharmaceutically acceptable excipient and a compound having a structure according to Formula II: 
in which the symbols Ar1 and Ar2 independently represent aryl, substituted aryl, heteroaryl and substituted heteroaryl. The letter represents 0, S or Nxe2x80x94R1, in which R1 is a H, (C1-C8)alkyl, substituted (C1-C8)alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, aryl(C1-C4)alkyl, substituted aryl(C1-C4)alkyl, CN, xe2x80x94C(O)R2, xe2x80x94OR3, xe2x80x94C(O)NR3R4, or xe2x80x94S(O)2NR3R4. The symbol R2 represents (C1-C8)alkyl, substituted (C1-C8)alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, aryl(C1-C4)alkyl or substituted aryl(C1-C4)alkyl. R3 and R4 are each members independently selected from the group consisting of hydrogen, (C1-C8)alkyl, substituted (C1-C8)alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, aryl(C1-C4)alkyl and substituted aryl(C1-C4)alkyl. Alternatively, R3 and R4 can be combined with the nitrogen to which each is attached to form a 5-, 6- or 7-membered ring optionally having additional heteroatoms at the ring vertices.
In a further aspect, the present invention provides compounds having a structure according to Formula III: 
In Formula III, the symbols Y1 and y2 independently represent H, methyl, methoxy, trifluoromethoxy, xe2x80x94CF3 or halo, with the proviso that both y1 and y2 are not H. The symbols V and X independently represent H, halo, substituted or unsubstituted lower alkyl, substituted or unsubstituted lower heteroalkyl, NO2, CN, CF3, C(O)NR11R12 and C(O)R13. The symbols R11, R12 and R13 independently represent substituted or unsubstituted lower alkyl, substituted or unsubstituted lower heteroalkyl, substituted or unsubstituted carbocycle, substituted or unsubstituted heterocycle, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. R11 and R12 can be joined into a ring. Q and W independently represent xe2x80x94(CR2R3)txe2x80x94(CH2)nxe2x80x94, -(CH2)nxe2x80x94(CR2R3)t, xe2x80x94C(R4)xe2x95x90C(R5)xe2x80x94, or xe2x80x94Cxe2x89xa1Cxe2x80x94 wherein R2 and R3 are independently F, substituted or unsubstituted lower alkyl or substituted or unsubstituted lower heteroalkyl, wherein R2 and R3 are optionally joined to form a cyclic structure which is a member selected from the group consisting of cycloalkyls and heterocycles, or R2 and R3 together with the carbon to which they are attached form carbonyl (i.e., xe2x80x94C(O)xe2x80x94). Q can optionally be a bond between the phenyl ring and Z, and W can optionally be a bond between Z and R1. The symbol Z represents xe2x80x94Oxe2x80x94, xe2x80x94S(O)mxe2x80x94, xe2x80x94N(R4)xe2x80x94, xe2x80x94N(R4)C(O)xe2x80x94, xe2x80x94C(O)N(R4)xe2x80x94, xe2x80x94C(O)xe2x80x94, xe2x80x94N(R4)C(O)N(R5)xe2x80x94, xe2x80x94N(R4)C(O)Oxe2x80x94, and xe2x80x94SO2N(R4)xe2x80x94, wherein R4 and R5 are members independently selected from the group consisting of H, substituted or unsubstituted lower alkyl, substituted or unsubstituted lower heteroalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. R1 is optionally joined together with either X or R4 to form a substituted or unsubstituted heterocycle. The symbol m represents an integer from 0 to 2, inclusive; n represents and integer from 0 and 3, inclusive; and t represents an integer from 0 to 2, inclusive.
In yet another aspect, the present invention provides a method for modulating ion flux through voltage dependent potassium channels, comprising contacting a cell containing the target ion channels with a compound according to Formulae I-IV.
In still another aspect, the present invention provides a method for the treatment of diseases through modulation of ion flux through voltage dependent potassium channels, the method comprising treating the host with an effective amount of a potassium channel opening compound of Formula I-IV.